Jochen Keupp

A Temperature-Sensitive Liposomal 1H CEST and 19F Contrast Agent for MR Image-Guided Drug Delivery

A novel temperature-sensitive liposomal MRI contrast agent has been developed, which allows drug carrier localization using (1)H CEST with simultaneous quantification of the drug release using (19)F MR imaging in response to a local temperature increase.

Iopamidol as a responsive MRI-chemical exchange saturation transfer contrast agent for pH mapping of kidneys: In vivo studies in mice at 7 T.

Iopamidol (Isovue®—Bracco Diagnostic Inc.) is a clinically approved X‐Ray contrast agent used in the last 30 years for a wide variety of diagnostic applications with a very good clinical acceptance. Iopamidol contains two types of amide functionalities that can be exploited for the generation of chemical exchange saturation transfer effect. The exchange rate of the two amide proton pools is markedly pH‐dependent. Thus, a ratiometric method for pH assessment has been set‐up based on the comparison of the saturation transfer effects induced by selective irradiation of the two resonances. This ratiometric approach allows to rule out the concentration effect of the contrast agent and provides accurate pH measurements in the 5.5–7.4 range. Upon injection of Iopamidol into healthy mice, it has been possible to acquire pH maps of kidney regions. Furthermore, it has been also shown that the proposed method is able to report about pH‐changes induced in control mice fed with acidified or basified water for a period of a week before image acquisition. Magn Reson Med, 2010.

Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades.

BACKGROUND Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas. METHODS Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1 ± 14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets ω = -6 to +6 ppm (step 0.5 ppm). δB0 maps were acquired separately for a point-by-point δB0 correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR)asym = (S[-3.5 ppm] - S[+3.5 ppm])/S0. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density. RESULTS The mean APT SI values were 2.1 ± 0.4% in grade II gliomas (n = 8), 3.2 ± 0.9% in grade III gliomas (n = 10), and 4.1 ± 1.0% in grade IV gliomas (n = 18). Significant differences in APT intensity were observed between grades II and III (P < .05) and grades III and IV (P < .05), as well as between grades II and IV (P < .001). There were positive correlations between APT SI and Ki-67 LI (P = .01, R = 0.43) and between APT SI and cell density (P < .05, R = 0.38). The gliomas with microscopic necrosis showed higher APT SI than those without necrosis (P < .001). CONCLUSIONS APT imaging can predict the histopathological grades of adult diffuse gliomas.

Dynamic and simultaneous MR measurement of R1 and R2* changes during respiratory challenges for the assessment of blood and tissue oxygenation

This work presents a novel method for the rapid and simultaneous measurement of R1 and R2* relaxation rates. It is based on a dynamic short repetition time steady‐state spoiled multigradient‐echo sequence and baseline R1 and B1 measurements. The accuracy of the approach was evaluated in simulations and a phantom experiment. The sensitivity and specificity of the method were demonstrated in one volunteer and in four patients with intracranial tumors during carbogen inhalation. We utilized (ΔR2*, ΔR1) scatter plots to analyze the multiparametric response amplitude of each voxel within an area of interest. In normal tissue R2* decreased and R1 increased moderately in response to the elevated blood and tissue oxygenation. A strong negative ΔR2* and ΔR1 response was observed in veins and some tumor areas. Moderate positive ΔR2* and ΔR1 response amplitudes were found in fluid‐rich tissue as in cerebrospinal fluid, peritumoral edema, and necrotic areas. The multiparametric approach was shown to increase the specificity and sensitivity of oxygen‐enhanced MRI compared to measuring ΔR2* or ΔR1 alone. It is thus expected to provide an optimal tool for the identification of tissue areas with low oxygenation, e.g., in tumors with compromised oxygen supply. Magn Reson Med, 2013.

Whole-body 3D water/fat resolved continuously moving table imaging†

To study the feasibility of three‐dimensional (3D) whole‐body, head‐to‐toe, water/fat resolved MRI, using continuously moving table imaging technology.

Continuously moving table SENSE imaging

A combination of continuously moving table imaging and parallel imaging based on sensitivity encoding (SENSE) is presented. One specific geometry is considered, where the receiver array is fixed to the MR magnet and does not move with the table, which allows for head‐to‐toe imaging with a small total number of coils. Sensitivity maps are defined for the enlarged virtual field of view and are composed according to the k‐space sampling scheme such that established parallel reconstruction techniques are applicable to good approximation. In vivo experiments show the feasibility of this approach, and simulations determine the application range. Three‐dimensional head‐to‐toe imaging of volunteers is performed in 77 s with a SENSE reduction factor of 2 in a virtual field of view of 1800 × 460 × 100 mm3. Magn Reson Med 53:217–220, 2005.

Simultaneous T1 measurements and proton resonance frequency shift based thermometry using variable flip angles

A method is presented which allows precise temperature and longitudinal (T1) relaxation time measurements with high spatial and temporal resolution. This is achieved by combining dynamic variable flip angle based T1 relaxation mapping with proton resonance frequency shift based thermometry. Herein, dynamic T1 mapping is either used as a complementary measure of temperature or for the detection of T1 contrast agent release. For the first application, the temperature evolution during a high‐intensity focused ultrasound tissue ablation experiment was measured in both, porcine fat and muscle, simultaneously. In this application, temperature accuracies of 2.5 K for T1‐based thermometry in fat and 1.2 K for proton resonance frequency shift‐based thermometry in muscle were observed. The second application relates to MR‐guidance of high‐intensity focused ultrasound‐induced local drug delivery by means of thermo‐sensitive liposomes labeled with a T1 contrast agent (Gd‐HPDO3A). When the measured temperature exceeded the phase transition temperature of the liposomes, T1 was observed to decrease with a good temporal and spatial correlation due to the release of Gd‐HPDO3A. The presented results demonstrate the feasibility of the proposed method for two important applications in MR‐guided noninvasive therapy. It offers a high temporal resolution when compared with interleaved Look‐Locker based T1 mapping techniques and thus represents an interesting candidate for simultaneous real‐time monitoring of T1 and temperature changes. Magn Reson Med, 2012.

Continuously moving table 3D MRI with lateral frequency-encoding direction

A method is presented for 3D MRI in an extended field of view (FOV) based on continuous motion of the patient table and an efficient acquisition scheme. A gradient‐echo MR pulse sequence is applied with lateral (left–right (L/R)) frequency‐encoding direction and slab selection along the direction of motion. Compensation for the table motion is achieved by a combination of slab tracking and data alignment in hybrid space. The method allows fast k‐space coverage to be achieved, especially when a short sampling FOV is chosen along the direction of table motion, as is desirable for good image quality. The method can be incorporated into different acquisitions schemes, including segmented k‐space scanning, which allows for contrast variation with the use of magnetization preparation. Head‐to‐toe images of volunteers were obtained with good quality using 3D spoiled gradient‐echo sequences. As an example of magnetization‐prepared imaging, fat/water separated images were acquired using chemical shift selective (CHESS) presaturation pulses. Magn Reson Med, 2006.

MR cholangiography demonstrates unsuspected rapid biliary clearance of nanoparticles in rodents: Implications for clinical translation

Due to their small size, lower cost, short reproduction cycle, and genetic manipulation, rodents have been widely used to test the safety and efficacy for pharmaceutical development in human disease. In this report, MR cholangiography demonstrated an unexpected rapid (<5 min) biliary elimination of gadolinium-perfluorocarbon nanoparticles (approximately 250 nm diameter) into the common bile duct and small intestine of rats, which is notably different from nanoparticle clearance patterns in larger animals and humans. Unawareness of this dissimilarity in nanoparticle clearance mechanisms between small animals and humans may lead to fundamental errors in predicting nanoparticle efficacy, pharmacokinetics, biodistribution, bioelimination, and toxicity. From the clinical editor: Comprehensive understanding of nanoparticle clearance is a clear prerequisite for human applications of nanomedicine-based therapeutic approaches. Through a novel use of MR cholangiography, this study demonstrates unusually rapid hepatic clearance of gadolinium-perfluorocarbon nanoparticles in rodents, in a pattern that is different than what is observed in larger animals and humans, raising awareness of important differences between common rodent-based models and larger mammals.

Balanced UTE-SSFP for 19F MR imaging of complex spectra.

A novel technique for highly sensitive detection of multiresonant fluorine imaging agents was designed and tested with the use of dual‐frequency 19F/1H ultrashort echo times (UTE) sampled with a balanced steady‐state free precession (SSFP) pulse sequence and three‐dimensional (3D) radial readout.